Review
Precision respiratory medicine and the microbiome

https://doi.org/10.1016/S2213-2600(15)00476-2Get rights and content

Summary

A decade of rapid technological advances has provided an exciting opportunity to incorporate information relating to a range of potentially important disease determinants in the clinical decision-making process. Access to highly detailed data will enable respiratory medicine to evolve from one-size-fits-all models of care, which are associated with variable clinical effectiveness and high rates of side-effects, to precision approaches, where treatment is tailored to individual patients. The human microbiome has increasingly been recognised as playing an important part in determining disease course and response to treatment. Its inclusion in precision models of respiratory medicine, therefore, is essential. Analysis of the microbiome provides an opportunity to develop novel prognostic markers for airways disease, improve definition of clinical phenotypes, develop additional guidance to aid treatment selection, and increase the accuracy of indicators of treatment effect. In this Review we propose that collaboration between researchers and clinicians is needed if respiratory medicine is to replicate the successes of precision medicine seen in other clinical specialties.

Introduction

The advent of precision medicine makes the next 10 years of clinical medicine incredibly exciting. With the availability of more detailed and comprehensive information on which to base treatment decisions, positive clinical outcomes become increasingly likely. A personalised or precision approach to medicine involves taking into account factors specific to an individual patient that identify the nature of their disease or disorder and the interventions that are most likely to be beneficial. The importance of such an approach might seem obvious, but efforts to standardise treatment and to ensure consistent levels of care, and the time required to assess wider contributors to disease, have meant that therapy is commonly defined by guidelines based on grouped clinical or physiological characteristics. This one-size-fits-all model of care makes the assumption that all patients with the same disorder, which could have arisen via several different pathways, will respond equally well to the same treatments. Furthermore, this approach necessarily accepts that treatment will be less than optimum for any but the average patient, and that side-effects, some severe, will occur in a substantial proportion of individuals.

The benefits of precision medicine have been shown clearly in relation to cancer. Technological advances over the past four decades have provided the ability to assess genetic material quickly and cheaply. In turn, it has become possible to tailor treatment to specific cancer genotypes.1 Recognition of the importance of this strategy has culminated in the National Institute of Health Precision Medicine Initiative Cohort Program. This project aims to build on the successful use of patients' genetic information to guide further improvements in cancer prevention and treatment.2

Despite the current high profile of personalised cancer therapy, oncology is a relative newcomer to precision medicine. By contrast, a precision approach has been the foundation of infectious disease management for well over a century,3 being based on the identification of causal agents and their antimicrobial susceptibility through axenic culture. Such culture-based analysis is widespread in respiratory medicine, including in disorders such as cystic fibrosis and chronic obstructive pulmonary disease (COPD).

Despite the importance of diagnostic microbiology, most respiratory clinicians would regard the use of patients' genetics to develop specific pharmacotherapies for cystic fibrosis, as the most high-profile example of precision medicine in respiratory disease. While giving rise to broadly comparable clinical phenotypes, nearly 2000 mutations in CFTR have been identified and represent an array of pathophysiological pathways and potential therapeutic targets, the complexity of which is compounded by around 40% of patients with cystic fibrosis being complex heterozygotes.4 The success of the CFTR potentiator, ivacaftor, in improving ion-channel regulation in patients with class III mutations (especially Gly551Asp) has been greatly encouraging.5 Research to identify agents, alone or in combination, that are effective for other genotypes in cystic fibrosis is continuing.6 Nevertheless, despite such success, the potential benefits of extending precision respiratory medicine beyond human genetics are clear. Even in a disorder such as cystic fibrosis, which results from a genetic mutation, genotype only explains around 50% of variation in pulmonary function. The remaining 50% is accounted for by stochastic and deterministic environmental influences,7 a substantial component of which is likely to stem from airway microbiology. Furthermore, the contribution of microbiological factors to differences between patients in disease course is probably even greater in disorders such as asthma and COPD, which have no overarching genetic basis, and where patients are grouped according to broad clinical and physiological characteristics.8

Key messages

  • The drive to improve clinical outcomes and reduce adverse events in respiratory medicine is becoming increasingly focused on precision approaches

  • Accumulating evidence suggests that interactions between host and microbiome contribute substantially to differences in clinical phenotypes and disease courses between patients

  • The potential for microbiome analysis to help stratify treatment and provide prognostic insight is beginning to be seen for several respiratory disorders

  • Continuing technological advances in areas such as metatranscriptomics and metabolomics are set to provide increasingly detailed and potentially informative data

  • The effective translation of microbiome analysis into precision models of respiratory care now requires concerted collaboration between researchers across various clinical and research disciplines

The detection of certain pathogens in airway samples can provide important prognostic markers and therapeutic targets for acute and chronic infections.9, 10 Why microbiological data have not featured more prominently in efforts to personalise respiratory medicine, therefore, needs to be considered. Exclusion is due mostly to the limitations of culture-based microbiology as applied diagnostically. Many common respiratory pathogens can exhibit phenotypes that limit their detection with standard protocols,11 whereas others, including strict anaerobes, require specialised sample-handling and growth conditions. Well described disparities between antibiotic susceptibility in vitro and treatment efficacy in vivo have led to the usefulness of routine testing in many chronic respiratory infections being questioned,12 with growing reliance on standardised antibiotic combinations. Arguably, with increasingly dogmatic approaches to treatment, a move has been seen away from precision respiratory medicine. Furthermore, although culture-based characterisation of individual pathogens can provide important insights into the likely disease course and clinical outcomes,13 axenic culture removes the potential for interspecies interactions that affect pathogen growth and virulence.14

Advances in DNA sequencing technology has, in parallel, led to progress in precision medicine and characterisation of complex microbial systems. Costs of microbiological analysis have not only reduced, but the use of sequencing for research has broadened, leading to substantial analytical and conceptual progress. By addressing many of the historical limitations of culture-based microbiology, sequencing approaches provide an opportunity to improve understanding of an important group of potential disease determinants—the complex microbial systems that are intimately associated with the human body.

In this Review, we make the case that rapid access to high-quality correlated respiratory microbiome information will add substantially to physicians' ability to make precise patient-centred treatment decisions. We discuss the evidence for the role of the human microbiome in respiratory disease, the implications for clinical decision making, and the importance of forging an effective link between advances in basic science and health-care delivery.

Section snippets

The human microbiome

The microbes that comprise the human microbiome are ecologically and immunologically integrated with our bodies, vastly exceeding our own cells both in number and genetic complexity.15 These intricate and interactive microbial networks, which consist of bacteria, fungi, viruses, bacteriophages, archaea, and eukaryotes, colonise niches all over the body. Unlike our genome, our microbiome is highly dynamic, changing as we grow and age,16 is spatially differentiated (ie, can be differentiated from

The respiratory microbiome as a guide to treatment

The compositions of the various microbiota in the human body are determined by the selective characteristics of the niches in which they grow.17 The lower airways, however, comprise a special case. Although exposed to the external environment and adjoining regions with commensal colonies, the lower airways are believed to be free from substantial resident microbial populations under normal circumstances, due to continual clearance through mucociliary action and phagocytosis preventing

The wider human microbiome and respiratory health

The interactions that occur between all mucosae and the microbiome are important determinants of general health.85 The role of the gut microbiota in the development and regulation of immunity in particular86, 87 suggests that these interactions contribute to differences in respiratory disease courses between individuals. We discuss here the effect of host–microbiome interactions in early life and how they affect immune regulation. We also explore the role of microbiota outside the lower

Challenges

The technological capacity available to analyse the microbiome is evolving rapidly. 16S rRNA gene sequencing is increasingly being replaced by more discriminatory shotgun metagenomic sequencing, which can accurately identify microbes and provide information on pathogenicity and antibiotic resistance markers. In turn, metatranscriptomic and metabolomic approaches that characterise microbial behaviour in response to changes in disease or therapy and capture an increased proportion of the

Conclusions and the future

Recognition of the importance of microbiome analysis is still growing, but it has clear potential to guide treatment, which suggests that it could become a central component in the management of respiratory disease, from first presentation to end stage or transplantation. For example, we suggest that in the near term, the ability to compare airway microbiota profiles with databases compiled from large groups of patients would increase accuracy of subtyping of respiratory conditions, and provide

Search strategy and selection criteria

References for this review were identified through searches of PubMed for articles published from January, 1971, to October, 2015, by use of the terms “asthma”, “COPD”, “cystic fibrosis”, “dysbiosis”, “idiopathic pulmonary fibrosis”, “infection”, “microbiome”, “microbiota”, “personalized”, “precision”, and “respiratory”. Articles resulting from these searches and relevant references cited in those articles were reviewed. Only English-language articles were included.

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